Chakravorty Debangana, Ghosh Abhirupa, Saha Sudipto
Division of Bioinformatics, Bose Institute, Kolkata, India.
Comput Biol Chem. 2020 Apr;85:107208. doi: 10.1016/j.compbiolchem.2020.107208. Epub 2020 Jan 27.
Myc is a crucial player in cellular proliferation and a known regulator of cancer pathobiology. Modulation of Myc expression targeting the Myc Protein-Protein Interactors (PPIs) like Myc-Max has till now been the most explored approach. However, this approach threatens the normal cells where Myc expression is required for proliferation. This demands the need for a new strategy to indirectly modulate Myc expression. Indirect modulation can be achieved by regulating Myc turnover. FBXW7 mediates the ubiquitination and subsequent degradation of Myc which is reversed by USP28. In this study, the interaction of USP28 with FBXW7 as well as with its substrate, Ubiquitin (Ub) were used as targets. Computation based high-throughput screening of bioactive small chemicals using molecular docking method was implemented to predict USP28 inhibitors. For the two regions, docking study with AutoDock Vina gave top 10 best scoring drugs which were identified and tabulated. The two regions defined in the study as FBXW7 binding and Ub binding also encompass the areas in which USP28 differed from USP25, a homologue with a different role. Out of these the best scoring drugs were explored for their role in cancer, if any. This study was performed keeping in mind re-purposing of these known drugs for possible alternative anti-Myc cancer therapy.
Myc是细胞增殖中的关键因子，也是癌症病理生物学中已知的调节因子。迄今为止，靶向Myc蛋白-蛋白相互作用分子（PPI）（如Myc-Max）来调节Myc表达是研究最多的方法。然而，这种方法会对正常细胞构成威胁，因为正常细胞的增殖需要Myc表达。这就需要一种新策略来间接调节Myc表达。间接调节可以通过调控Myc的周转来实现。FBXW7介导Myc的泛素化及随后的降解，而USP28可逆转这种降解。在本研究中，将USP28与FBXW7以及与其底物泛素（Ub）的相互作用作为靶点。采用分子对接方法对生物活性小分子进行基于计算的高通量筛选，以预测USP28抑制剂。针对这两个区域，使用AutoDock Vina进行对接研究，得出得分最高的前10种药物，并进行了鉴定和列表。研究中定义的FBXW7结合区域和Ub结合区域也包含了USP28与其同源物USP25不同的区域，USP25具有不同的作用。从中探究了得分最高的药物在癌症中的作用（如果有）。本研究进行时考虑到将这些已知药物重新用于可能的替代性抗Myc癌症治疗。
